chr12-88093947-C-A

Variant names:

• chr12-88093947-C-A
• rs762342726
• NM_025114.4:c.3132G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025114.4(CEP290):​c.3132G>T​(p.Lys1044Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1044E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CEP290 NM_025114.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0740
• Publications: 4 publications found

Genes affected

CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]

CEP290 Gene-Disease associations (from GenCC):

• CEP290-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Leber congenital amaurosis 10

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025114.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	NM_025114.4	MANE Select	c.3132G>T	p.Lys1044Asn	missense	Exon 28 of 54	NP_079390.3	O15078

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP290	ENST00000552810.6	TSL:1 MANE Select	c.3132G>T	p.Lys1044Asn	missense	Exon 28 of 54	ENSP00000448012.1	O15078
	CEP290	ENST00000547691.8	TSL:1	c.414G>T	p.Lys138Asn	missense	Exon 4 of 28	ENSP00000446905.3	A0A5K1VW81
	CEP290	ENST00000604024.5	TSL:1	c.2391G>T	p.Lys797Asn	missense	Exon 20 of 20	ENSP00000473863.1	S4R322

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246924 AF XY: 0.00000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459328 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725918

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111080

Other (OTH) AF: 0.0000166 AC: 1 AN: 60248

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Meckel-Gruber syndrome;C0687120:Nephronophthisis;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.074
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.043
Sift	Benign	0.34	T
Sift4G	Benign	0.50	T
Polyphen		0.050	B
Vest4		0.27
MutPred		0.16		Loss of ubiquitination at K1044 (P = 0.0155)
MVP		0.63
MPC		0.083
ClinPred		0.14	T
GERP RS		0.0088
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.18
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762342726; hg19: chr12-88487724; COSMIC: COSV58351236;